Reduced Intensity Allogeneic Stem Cell Transplant In Patients With Multiple Myeloma: A Comparison Of Planned Autologous-Reduced Intensity Allogeneic Stem Cell Transplant (Auto-Allo) and Reduced Intensity Allogeneic Stem Cell Transplant (RIC) As Upfront Transplant In Patients With Multiple Myeloma, An EBMT Analysis

Despite the advances in the treatment of multiple myeloma using new targeted therapies and autologous hematopoietic stem cell transplant (HSCT) the disease remains largely incurable. Recent efforts in using reduced intensity allogeneic HSCT have been hampered by increased allograft-related morbidity and mortality. Several prospective studies comparing single or tandem autologous HSCT with planned tandem autologous-reduced intensity allogeneic HSCT (auto-allo) have shown no overall survival advantage despite improvements in progression-free survival (PFS) and lower relapse rates with reduced intensity allograft, mainly due to increased non-relapse related mortality (NRM) rates. However, two of these prospective studies; the European Group for Blood and Marrow Transplantation NMAM 2000 and the Italian group study with long term follow-up reported PFS and overall survival (OS) benefits in favor of the auto-allo arm. Currently allogeneic HSCT is recommended within the context of clinical trials and only in high risk multiple myeloma patients who continue to have a very poor outcome with autologous HSCT. While such clinical trials are ongoing there remains a need to address the role of autologous HSCT prior to reduced intensity allogeneic HSCT. The objective of this retrospective study is to evaluate the role of upfront cytoreductive autologous HSCT prior to allograft in the outcomes of patients who have undergone allograft following induction therapy.

We performed a retrospective analysis of the EBMT database comparing the outcomes of patients who were planned to receive auto-allograft to those who underwent reduced intensity allograft (early RIC) without a prior autologous HSCT within one year from diagnosis. The data in 504 patients were previously reported at the ASH meeting 2010 (abstract 3512). We subsequently included additional patients and requested more information from the participating EBMT centers and updated the study. From 1996 to 2013 a total of 689 patients were registered as reduced intensity allograft. 517 patients were registered as planned auto-allograft; however, 73 did not receive the planned allograft. A total of 172 patients received reduced intensity allograft after induction treatment without prior auto-HSCT. Median age at first transplant was 53 years (range 20-72) in the auto-allo and 51 years (range 31-77) in the early RIC group. Median time from diagnosis was 6.6 months (range 2-156 months) in the auto-allo and 7.7 months (2.8-12.0) in the early RIC group. The disease status at the time of first transplant for the auto-allo group was CR - 8%, PR - 67%, other or missing - 25%; and for the RIC group was CR - 15%, PR - 62%, other or missing - 23%. Donors were HLA matched siblings in 88% and matched unrelated in 12% for the auto-allo group, and 84% siblings and 16% matched unrelated in the RIC group with no significant differences between the two groups.

With a median follow-up of 93 months in the auto-allo and 84 months in RIC groups, PFS rates were significantly better at 3 and 5 years in the auto-allo group (45.6% and 34.2%) as compared to the RIC group (33.9% and 22.0%, p<0.001). Overall survival was also significantly improved in favor of the auto-allo (3 yr and 5 yr OS 67.9% and 58.9%) as compared to the RIC group (54.3% and 42.7%, P = 0.001). The non-relapse mortality (NRM) rates were lower in the auto-allo group as compared to RIC: 1 yr and 3 yr NRM were 8.1% and 14.1% in the auto-allo and 20.3% and 27.4% in early RIC group, p<0.001. We examined potential differences in outcomes based on use of novel agents, and used the year 2004 as a surrogate for introduction of novel agents to routine clinical practice. There were no significant differences by multivariate analysis in outcomes for patients transplanted before or after 2004.

This large multicenter retrospective study suggests that cytoreductive autologous HSCT prior to allograft is associated with improved PFS and OS. We are in the process of conducting an extended analysis to control for possible confounders. If the results are confirmed, future studies should be conducted to verify the importance of autologous stem cell transplant as part of the allograft treatment strategy.

No relevant conflicts of interest to declare.